This invention relates to novel imidazopyridine compounds. These compounds have 5-HT4 receptor binding activity (e.g., agonist or antagonist activities), and thus are useful for the treatment of or prevention of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety, cardiovascular disorder or the like, in mammalian, especially human. The present invention also relates to a pharmaceutical composition comprising the above compounds.
Serotonin (5-HT) receptors are known to have a plurality of subtypes such as 5-HT1, 5-HT2, 5-HT3 and 5-HT4. These 5-HT4 receptors are disclosed in, for example, European Journal of Pharmacology 146 (1988), 187-188, and Naunyn-Schmiedeberg""s Arch. Pharmacol. (1989) 340:403-410.
5-HT4 receptor modulators (e.g., agonists and antagonists) are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arryhthmia (See TiPs, 1992, 13, 141; Ford A. P. D. W. et al., Med. Res. Rev., 1993, 13, 633; Gullikson G. W. et al., Drug Dev. Res., 1992, 26, 405; Richard M. Eglen et al, TiPS, 1995, 16, 391; Bockaert J. et al., CNS Drugs, 1, 6; Romanelli M. N. et al., Arzheim Forsch./Drug Res., 1993, 43, 30 913; Kaumann A. et al., Naunyn-Schmiedeberg""s. 1991, 344, 150; and Romanelli M. N. et al., Arzheim Forsch./Drug Res., 1993, 43, 913).
A variety of imidazopyridine compounds have been known as 5HT receptor antagonists or agonists. For example, Japanese Patent Publication Laid-Open No. H01-258,674 and H02-643,274 disclose imidazopyridine compounds as 5HT receptor antagonists. WO 96/05166 discloses imidazopyridine compounds as 5HT4 agonists. WO92/15593; U.S. Pat. No. 5,260,303; U.S. Pat. No. 5,604,239; U.S. Pat. No. 5,591,749; U.S. Pat. No. 5,219,850; U.S. Pat. No. 5,434,161; U.S. Pat. No. 5,137,893; U.S. Pat. No. 5,196,547; and EP 504679 describe a variety of imidazopyridine compounds as 5HT3 receptor antagonists. WO94/08998 discloses imidazopyridine compounds as 5HT4 receptor antagonists.
Also, imidazopyridine compounds synthesized for different uses are described in JP2001/6877; WO01/5763; WO 99/50247; WO 97/27852, WO 9738665 and EP 274867.
It would be desirable if there were provided 5HT4 receptor modulators (e.g., agonists and antagonists) which have more 5HT4 receptor modulating activities (e.g., angonist or antagonist activities).
The present invention provides a compound of the following formula (I): 
or the pharmaceutically acceptable salts thereof wherein
R1 is hydrogen, halo or C1-6 alkyl;
R2and R3 are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, mono- or di-(C1-5)alkyl amino, amino(C1-5)alkyl or hydroxy(C1-5)alkyl; or R2and R3taken together with the nitrogen atom to which they are attached may form substituted or non-substituted nitrogen-containing hetrocyclic;
R4 is hydrogen, halo, C1-8 acyl, amino, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C1-6)alkyl, or substituted or non-substituted heterocyclic;
R5 is hydrogen, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-8 acyl, amino, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C1-6)alkyl, or substituted or non-substituted heterocyclic;
R6 is hydrogen, C1-6 alkyl or C1-6 alkoxy (C1-6)alkyl;
X is NR9 wherein R9 is hydrogen or C1-6 alkyl; and
Y is (CR7R8)n wherein R7and R8 are independently hydrogen or C1-6 alkyl, and n is an integer from 0 to 5.
The imidazopyridine compounds of this invention have 5-HT4 receptor modulating activities (e.g., an antagonistic or agonistic function towards 5-HT4 receptor), and are thus useful for the treatment or prevention of disease conditions mediated by 5-HT4 receptor activities.
Thus, the present invention provides a pharmaceutical composition for the treatment of disease conditions mediated by 5-HT4 receptor activities, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety, cardiovascular disorders such as cardiac failure and heart arryhthmia, or the like, which comprises a therapeutically effective amount of the imidazopyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of disease conditions mediated by 5-HT4 receptor activities, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). Further, the present invention provides a method for the treatment of the disease conditions as mentioned above. Furthermore, the present invention provides use of the compound of formula (I) in the manufacture of a medicament for the treatment or prevention of disease conditions mediated by 5-HT4 receptor activity, in a mammalian subject. The conditions mediated by 5-HT4 receptor activity are those diseases or disorders described as above.
As used herein, the term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl.
As used herein, the term xe2x80x9calkenylxe2x80x9d means a hydrocarbon radical having at least one double bond including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
As used herein, the term xe2x80x9calkynylxe2x80x9d means a hydrocarbon radical having at least one triple bond including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94, including, but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secondary-butoxy, tertiary-butoxy.
As used herein, the term xe2x80x9cacylxe2x80x9d means a group having carbonyl such as Rxe2x80x2xe2x80x3xe2x80x94C(O)xe2x80x94 wherein Rxe2x80x2xe2x80x3 is C1-5 alkyl, phenyl or C3-7 cycloalkyl, including, but not limited to formyl, acetyl, ethyl-C(O)xe2x80x94, n-propyl-C(O)xe2x80x94, isopropyl-C(O)xe2x80x94, n-butyl-C(O)xe2x80x94, iso-butyl-C(O)xe2x80x94, secondary-butyl-C(O)xe2x80x94, tertiary-butyl-C(O)xe2x80x94, cyclopropyl-C(O)xe2x80x94, cyclobutyl-C(O)xe2x80x94, cyclopentyl-C(O)xe2x80x94, cyclohexyl-C(O)xe2x80x94, cycloheptyl-C(O)xe2x80x94, and the like.
As used herein, the term xe2x80x9cnitrogen-containing heterocyclicxe2x80x9d means 5- to 10-membered monocyclic or bicyclic rings having at least one nitrogen ring atom, including, but not limited to, a heterocyclic ring selected from morpholino, piperazino, piperidino, pyrrolidino, azetidino, pyrazolidino, (1,2,3,4)-tetrahydroisoqunolino and perhydroisoquinolino, preferably morpholino, piperazino and piperidino.
As used herein, the term xe2x80x9carylxe2x80x9d means a monocyclic or bicyclic aromatic carbocyclic ring of 6 to 11 carbon atoms including, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl, preferably phenyl and naphthyl.
As used herein, the term xe2x80x9carylalkylxe2x80x9d means an alkyl radical which is substituted by an aryl group as defined above.
As used herein, the term xe2x80x9cheterocyclicxe2x80x9d means a 5- to 10-membered monocyclic or bicyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. Examples of the heterocyclics include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4a H-carbazole, carbazole, .beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Preferable heterocyclic groups include piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl.
As used herein, the term xe2x80x9csubstituted nitrogen-containing heterocyclic, substituted aryl, substituted arylalkyl or substituted heterocyclicxe2x80x9d means those groups which are substituted with one to three (preferably one to two) substituents selected from halo, alkyl, amino, hydroxy, cyano, mono- or di-alkylamino, alkoxy, and alkoxyalkyl.
As used herein, the term xe2x80x9cmodulatorxe2x80x9d means compounds, agonists, antagonists, ligands, substrates and enzymes, which directly or indirectly affect regulation of the receptor activity.
In the compounds of formula (I), R1 is preferably hydrogen, halo or C1-3 alkyl, more preferably hydrogen or halo.
In the compounds of formula (I), R2 and R3 are preferably hydrogen, C1-3 alkyl, mono- or di-(C1-5)alkyl amino, amino(C1-5)alkyl or hydroxy(C1-5)alkyl; or R2 and R3 taken together with the nitrogen atom to which they are attached may form a substituted or non-substituted nitrogen-containing hetrocyclic ring; more preferably hydrogen or C1-3 alkyl; or R2 and R3 taken together with the nitrogen atom to which they are attached may form hetrocyclic selected from morpholino, piperazino, piperidino, pyrrolidino, azetidino, pyrazolidino, (1,2,3,4)-tetrahydroisoqunolino and perhydroisoquinolino, which may be optionally substituted with halo, C1-3 alkyl, C1-3 alkoxy, mono- or di-(C1-3)alkyl amino or C1-3 alkoxy(C1-3) alkyl; and most preferably hydrogen or C1-3 alkyl; or R2 and R3 taken together with the nitrogen to which they are attached may form hetrocyclic selected from morpholino, piperazino and piperidino.
In the compounds of formula (I), R4 is preferably hydrogen, halo, C1-3 acyl, substituted or non-substituted aryl, substituted or non-substituted aryl(C1-3)alkyl, or substituted or non-substituted heterocyclic; more preferably hydrogen, halo, C1-3 alkyl, C1-3 acyl, aryl selected from phenyl and naphthyl, arylalkyl selected from phenyl C1-3 alkyl and naphthyl C1-3 alkyl, or heteroaryl selected from piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl, wherein said aryl, arylalkyl or heteroaryl may optionally be substituted with halo, C1-3 alkyl, C1-3 alkoxy, mono- or di-(C1-3)alkyl amino or C1-3 alkoxy(C1-3) alkyl; more preferably hydrogen, halo, C1-3 alkyl, C1-3 acyl, phenyl, naphthyl, benzyl, piperidino, morpholino, pyrrolidino, pyrazolino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl and pyrrolyl; and most preferably hydrogen, halo or C1-3 alkyl.
In the compounds of formula (I), R5 is preferably hydrogen, halo, C1-3 alkyl, C1-3 acyl, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C1-3)alkyl, or substituted or non-substituted heterocyclic; more preferably hydrogen, halo, C1-3 alkyl, C1-3 acyl, aryl selected from phenyl and naphthyl, arylalkyl selected from phenyl C1-3 alkyl and naphthyl C1-3 alkyl, or heteroaryl selected from piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl, wherein said aryl, arylalkyl or heteroaryl may optionally be substituted with halo, C1-3 alkyl, C1-3 alkoxy, mono- or di-(C1-3)alkyl amino or C1-3 alkoxy(C1-3) alkyl; more preferably hydrogen, halo, C1-3 alkyl, C1-3 acyl, phenyl, naphthyl, benzyl, piperidino, morpholino, pyrrolidino, pyrazolino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl and pyrrolyl; and most preferably hydrogen, halo or C1-3 alkyl.
In the compounds of formula (I), R6 is preferably hydrogen, C1-5 alkyl or C1-3 alkoxy (C1-5)alkyl; preferably C1-5 alkyl or C1-3 alkoxy (C1-5)alkyl; more preferably C1-4 alkyl or C1-3 alkoxy (C1-4)alkyl; and preferably C3-4 alkyl or methoxy (C1-4)alkyl.
In the compounds of formula (I), X is preferably NR9, wherein R9 is independently hydrogen or C1-3 alkyl; more preferably NR9, wherein R9 is independently hydrogen or methyl; most preferably NH.
In the compounds of formula (I), Y is preferably (CR7R8)n, wherein R7 and R8 are independently hydrogen or C1-3 alkyl, and n is an integer from 0 to 3, more preferably (CR7R8)n (wherein R7and R8 are independently hydrogen or methyl, and n is an integer from 0 to 2; most preferably chemical bond or methylene.
Preferred compounds of this invention are those of the formula (I) wherein
R1 is hydrogen, halo or C1-3 alkyl;
R2 and R3 are independently hydrogen, C1-3 alkyl, mono- or di-(C1-5)alkyl amino, amino(C1-5)alkyl or hydroxy(C1-5)alkyl; or R2 and R3 taken together with the nitrogen atom to which they are attached may form substituted or non-substituted nitrogen-containing hetrocyclic;
R4 is hydrogen, halo, C1-3 acyl, substituted or non-substituted aryl, (C1-3)alkyl, or substituted or non-substituted heterocyclic;
R5 is hydrogen, halo, C1-3 alkyl, C1-3 acyl, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C1-3)alkyl, or substituted or non-substituted heterocyclic;
R6 is hydrogen, C1-5 alkyl or C1-3 alkoxy (C1-5)alkyl;
X is NR9; and Y is (CR7R8)n, wherein R7, R8 and R9 are independently hydrogen or C1-3 alkyl, and n is an integer from 0 to 3.
More preferred compounds of this invention are those of the formula (I) wherein
R1 is hydrogen or halo;
R2 and R3 are independently hydrogen or C1-3 alkyl; or R2 and R3 taken together with the nitrogen atom to which they are attached may form hetrocyclic selected from morpholino, piperazino, piperidino, pyrrolidino, azetidino, pyrazolidino, (1,2,3,4)-tetrahydroisoqunolino and perhydroisoquinolino, which may be optionally substituted with halo, C1-3 alkyl, C1-3 alkoxy, mono- or di-(C1-3)alkyl amino or C1-3 alkoxy(C1-3) alkyl;
R4 is hydrogen, halo, C1-3 acyl, aryl selected from phenyl and naphthyl, arylalkyl selected from phenyl C1-3 alkyl and naphthyl C1-3 alkyl, or heteroaryl selected from piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl, wherein said aryl, arylalkyl or heteroaryl may optionally be substituted with halo, C1-3 alkyl, C1-3 alkoxy, mono- or di-(C1-3)alkyl amino or C1-3 alkoxy(C1-3) alkyl;
R5 is hydrogen, halo, C1-3 alkyl, C1-3 acyl, amido, aryl selected from phenyl and naphthyl, arylalkyl selected from phenyl C1-3 alkyl and naphthyl C1-3 alkyl, or heteroaryl selected from piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl, wherein said aryl, arylalkyl or heteroaryl may optionally be substituted with halo, C1-3 alkyl, C1-3 alkoxy, mono- or di-(C1-3)alkyl amino or C1-3 alkoxy(C1-3) alkyl;
R6 is C1-5 alkyl or C1-3 alkoxy (C1-5)alkyl;
X is NR9; and Y is (CR7R8)n, wherein R7, R8 and R9 are independently hydrogen or methyl, and n is an integer from 0 to 2.
Also, preferred compounds of this invention are those of the formula (I) wherein
R1 is halo;
R2 and R3 are independently hydrogen, C1-3 alkyl; or R2 and R3 taken together with the nitrogen to which they are attached may form hetrocyclic selected from morpholino, piperazino and piperidino;
R4 is hydrogen, halo, C1-3 acyl, phenyl, naphthyl, benzyl, piperidino, morpholino, pyrrolidino, pyrazolino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl and pyrrolyl;
R5 is hydrogen, halo, C1-3 alkyl, C1-3 acyl, amido, phenyl, naphthyl, benzyl, piperidino, morpholino, pyrrolidino, pyrazolino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl and pyrrolyl;
R6 is C1-4 alkyl or C1-3 alkoxy (C1-4)alkyl;
X is NH; and
Y is chemical bond or methylene.
Also, more preferred compounds of this invention are those of the formula (I) wherein
R1 is chloro; R2 and R3 are independently hydrogen or C1-3 alkyl; R4 is hydrogen or halo; R5 is hydrogen, halo or C1-3 alkyl; R6 is C3-4 alkyl or methoxy (C1-4)alkyl; X is NH; and Y is methylene.
Preferred individual compounds of this invention are:
5-amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloroimidazo[1,2-a]pyridine-8-carboxamide;
5-amino-N-[(1-butyl-4-piperidinyl)methyl]imidazo[1,2-a]pyridine-8-carboxamide;
5-amino-6-chloro-N-[(1-(3-methoxypropyl)-4-piperidinyl]imidazo[1,2-a]pyridine-8-carboxamide;
5-amino-N-[(1-(3-methoxypropyl)-4-piperidinyl]imidazo[1,2-a]pyridine-8-carboxamide;
5-Amino-N-[(1-butyl-4-piperidiny)methyl]-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxamide;
5-Amino-6-chloro-2-methyl-N-{1-[3-(methyloxy)propyl]-4-piperidinyl}imidazo[1,2-a]pyridine-8-carboxamide;
5-Amino-6-chloro-2-methyl-N-({1-[3-(methyloxy)propyl]-4-piperidinyl}methyl)imidazolo[1,2-a]pyridine-8-carboxyamide; and salts thereof.
Other preferred individual compounds of this invention are:
5-amino-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-a]pyridine-8-carboxamide;
5-amino-6-chloro-N-{[1-(3,3-dimethylbutyl)piperidin-4-yl]methyl}-2-ethylimidazo[1,2-a]pyridine-8-carboxamide;
5-amino-6-chloro-2-ethyl-N-{[1-(2-methoxy-2-methylpropyl)piperidin-4-yl]methyl}imidazo[1,2-a]pyridine-8-carboxamide;
5-amino-6-chloro-2-methyl-N-{[1-(2-methoxy-2-methylpropyl)piperidin-4-yl]methyl}imidazo[1,2-a]pyridine-8-carboxamide; and
5-amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-a]pyridine-8-carboxamide; and salts thereof.
The imidazopyridine compounds of formula (I) of this invention may be prepared by a variety of synthetic methods. For example, the imidazopyridine compounds of formula (I) wherein X is NH, may be prepared by saponification of a carboxylate compound (II) to obtain a corresponding carboxylic acid compound (III), followed by a coupling reaction of the compound (III) with an amine compound (IV), as indicated in the following Scheme 1. 
wherein Rxe2x80x2 is C1-3 alkyl or benzyl; X is NH; and all other symbols are as already defined)
In Scheme 1, the carboxylate compound (II) may be first subjected to saponification of the ester residue at the 8-position of the imidazopyridine ring, followed by acidification to afford a corresponding carboxylic acid (III). Then, the compound (III) may be coupled with the amine compound (IV) to give an imidazopyridine compound (I) wherein X is NH.
The saponification and the acidification may be carried out by conventional procedures. In a typical procedure, the saponification is carried out by treatment with sodium hydroxide or lithium hydroxide in a suitable reaction-inert solvent. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethlene gylcol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and 1,4-dioxane; halogenated hydrocarbons such as chloroform, dichloroethane, and 1,2-dichloroethane; amides such as N,N-dimethylformamide (DMF) and hexamethylphospholictriamide; and sulfoxides such as dimethyl sulfoxide (DMSO). This reaction may be carried out at a temperature in the range from xe2x88x9220 to 100xc2x0 C., usually from 20xc2x0 C. to 65xc2x0 C. for 30 minutes to 24 hours, usually 60 minutes to 10 hour. In a typical procedure, the acidification is carried out by treatment with diluted hydrochloric acid or 10% aqueous citric acid in a suitable reaction-inert solvent such as water at a temperature in the range from xe2x88x9220 to 65xc2x0 C., usually from 0xc2x0 C. to 30xc2x0 C. for 30 minute to 10 hour, usually 30 minutes to 2 hours.
The coupling reaction may be carried out in the presence of a suitable condensation agent in a reaction-inert solvent. Suitable condensation agents include 1,1xe2x80x2-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC), 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylatetriphenylphosphine, diethylcyanophosphonate (DEPC), diphenylphosphorylazide (DPPA), bromotripyrrolidino phosphonium hexafluorophosphate (PyBrop[trademark]), bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), 2-(1-H-benzotriazole-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU) and ethyl chloroformate. Suitable reaction-inert solvents include aqueous or non-aqueous organic solvents such as tetrahydrofuran, N,N-dimethylformamide (DMF), dioxane, acetone, dimethoxyethane and acetonitrile; and halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane (preferably dichloromethane). This reaction may be carried out at a temperature in the range from xe2x88x9220 to 80xc2x0 C., usually from 0xc2x0 C. to 30xc2x0 C. for 30 minutes to 100 hours, usually 5 hours to 24 hours.
Scheme 2:
The carboxylate compounds (II) used as starting materials in Scheme 1 may be prepared in the following reaction steps. 
In Scheme 2, a nicotinate compound (V) wherein Rxe2x80x2 is C1-3 alkyl or benzyl and Z is halogen; and the amino group is protected by a pivaloyl group, may be reacted with an amine compound: NHR2R3, to obtain a compound (VI). This reaction is generally carried out at a pressure from 1 to 5 atmospheres, preferably at 1 to 4 atmospheres. This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol and ethlene gylcol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, diphenyl ether and 1,4-dioxane; halogenated hydrocarbons such as chloroform, dichloroethane and 1,2-dichloroethane; amides such as N,N-dimethylformamide and hexamethylphospholictriamide; sulfoxides such as dimethyl sulfoxide; acetonitrile; benzene, toluene, xylene; and pyridine. This reaction may be carried out at a temperature in the range from 20 to 100xc2x0 C., usually from 50xc2x0 C. to 80xc2x0 C. for 30 minutes to 24 hours, usually 30 minutes to 10 hours. When R1 is halo, the compound (VI) is treated with halogen or N-halogenated succimide or SELECTFLUOR(trademark) under appropriate conditions, to obtain a compound (VII) wherein R1 is halo. This reaction can be carried out in a suitable reaction-inert solvent such as carboxylic acids (e.g., acetic acid, propionic acid and butylic acid); halogenated hydrocarbons such as chloroform, dichloroethane and 1,2-dichloroethane; amides such as N,N-dimethylformamide and hexamethylphospholictriamide; sulfoxides such as dimethyl sulfoxide; acetonitrile; benzene, toluene, xylene; and pyridine. This reaction may be carried out at a temperature in the range from 0 to 80xc2x0 C., usually from 25 to 70xc2x0 C. for 5 minutes to 24 hours, usually 15 minutes to 8 hours. Then, the compound (VII) may be subject to deprotection of an amino-protecting group, to obtain a compound (VIII). The deprotection may be carried out in the presence of base (e.g., potassium tert-butoxide, sodium ethoxide and sodium hydroxide) or acids (e.g., hydrochloric acid and sulfuric acid). The deprotection can be carried out in a suitable reaction-inert solvent such as methanol at a temperature in the range from 25 to 80xc2x0 C., usually from 50 to 65xc2x0 C. for 10 minutes to 24 hours, usually 30 minutes to 10 hours.
Then, the compound (VIII) may be reacted with a compound (IX) wherein Xxe2x80x2 is halogen, to obtain a compound (II) and a compound (X). This reaction can be carried out in the presence of 2-halogenated aldehyde or 2-halogenated ketone (compound (IX)) in a suitable reaction-inert solvent such as methanol, ethanol, propanol and butanol at a temperature in the range from 25 to 120xc2x0 C., usually from 50xc2x0 C. to 65xc2x0 C. for 8 hours to 72 hours, usually 8 hours to 24 hours. The resulting mixture of the compound (II) and the compound (X) may be subjected to conventional separation techniques to obtain the compound (II). Suitable conventional separation techniques include silica gel column chromatography.
In addition, starting compounds of formula (V) are known or may be prepared from a known compound according to procedures known to those skilled in the art.
Scheme 3:
Compounds (Ixe2x80x2) (Compound (I) wherein R1 is hydrogen) can be prepared by subjecting a compound (I) wherein R1 is halo, to catalytic hydrogenation. 
In Scheme 3, the catalytic hydrogenation can be carried out in the presence of hydrogen or hydrogen source such as ammonium formate, and a suitable metal containing catalysts such as palladium, platinum, nickel, platinum oxide and rhodium in a suitable reaction-inert solvent such as methanol. The preferred catalyst is palladium on carbon. This hydrogenation can be carried out at a temperature in the range from 20 to 100xc2x0 C., usually from 25xc2x0 C. to 80xc2x0 C. for 5 minutes to 48 hours, usually 30 minutes to 2 hours. 
In scheme 4, the compound (Vxe2x80x2) may be reacted with an ammonia water to obtain a compound (XIV). This reaction is generally carried out in a sealed tube. This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol and ethlene gylcol; ethers such as THF, DME, diethyl ether, diisopropyl ether, diphenyl ether and 1,4-dioxane; halogenated hydrocarbons such as chloroform, dichloroethane and 1,2-dichloroethane; amides such as DMF and hexamethylphospholictriamide; sulfoxides such as DMSO; acetonitrile; benzene, toluene, xylene; and pyridine. This reaction may be carried out at a temperature in the range from 30 to 150xc2x0 C., usually from 50xc2x0 C. to 100xc2x0 C. for 30 minutes to 24 hours, usually 30 minutes to 12 hours. Compounds (IIxe2x80x2) may be prepared by reacting a compound (XIV) with the compound (IX) under appropriate conditions. This reaction can be carried out in a suitable reaction-inert solvent such as methanol. This reaction may be carried out at a temperature in the range from 25 to 65xc2x0 C., usually from 50xc2x0 C. to 65xc2x0 C. for 30 minutes to 48 hours, usually 30 minutes to 12 hours.
Scheme 5:
The nicotinate compounds (V) and (Vxe2x80x2) used as starting materials in Scheme 2,4,6 and 7 may be prepared in the following reaction steps. 
In scheme 5, a pyridine compound (XI) wherein R1 is C1-6 alkyl and Z is halogen, may be reacted with an ammonia water to obtain a compound (XII). This reaction is generally carried out in a sealed tube. This reaction may be carried out at a temperature in the range from 50 to 200xc2x0 C., usually from 100xc2x0 C. to 160xc2x0 C. for 30 minutes to 24 hours, usually 30 minutes to 12 hours. The compound (XII) is treated with pivaloyl chloride in the presence of base, such as diisopropylethylamine, triethylamine, pyridine and lutidine to obtain a mixture of compound (XIII). This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, halogenated hydrocarbons such as chloroform, dichloroethane and 1,2-dichloroethane. This reaction may be carried out at a temperature in the range from xe2x88x9220 to 50xc2x0 C., usually from xe2x88x9210xc2x0 C. to 30xc2x0 C. for 30 minutes to 24 hours, usually 30 minutes to 10 hours. The compound (XII) is treated with n-BuLi followed by ethyl chloroformate or carbobenzyloxychloride to obtain a compound (V) and (Vxe2x80x2). This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, diphenyl ether and 1,4-dioxane. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 50xc2x0 C., usually from xe2x88x92100 to 20xc2x0 C. for 5 minutes to 24 hours, usually 15 minutes to 8 hours. In addition, starting compounds of formula (XI) are known or may be prepared from a known compound according to procedures known to those skilled in the art, for example, Helv. Chim. Acta (1976), 59, 229-35, J. Chem. Soc., Perkin Trans. 1 (1996), 519-24 and J. Chem. Soc., Chem. Commun. (1988), 1482-3.
Scheme 6:
The carboxylate compounds (II) used as starting materials in Scheme 1 may be prepared in the following reaction steps. 
In Scheme 6, a nicotinate compound (V) wherein R1 is C1-6 alkyl, Rxe2x80x2 is C1-3 alkyl or benzyl and Z is halogen; and the amino group is protected by a pivaloyl group, may be reacted with an amine compound: NHR2R3, to obtain a compound (VII). This reaction is generally carried out at a pressure from 1 to 5 atmospheres, preferably at 1 to 4 atmospheres. This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol and ethlene gylcol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, diphenyl ether and 1,4-dioxane; halogenated hydrocarbons such as chloroform, dichloroethane and 1,2-dichloroethane; amides such as N,N-dimethylformamide and hexamethylphospholictriamide; sulfoxides such as dimethyl sulfoxide; acetonitrile; benzene, toluene, xylene; and pyridine. This reaction may be carried out at a temperature in the range from 20 to 100xc2x0 C., usually from 50xc2x0 C. to 80xc2x0 C. for 30 minutes to 24 hours, usually 30 minutes to 10 hours. Then, the compound (VII) may be subject to deprotection of an amino-protecting group, to obtain a compound (VII). The deprotection may be carried out in the presence of base (e.g., potassium tert-butoxide, sodium ethoxide and sodium hydroxide) or acids (e.g., hydrochloric acid and sulfuric acid). The deprotection can be carried out in a suitable reaction-inert solvent such as methanol at a temperature in the range from 25 to 80xc2x0 C., usually from 50 to 65xc2x0 C. for 10 minutes to 24 hours, usually 30 minutes to 10 hours.
Then, the compound (VIII) may be reacted with a compound (IX) to obtain a compound (II) and a compound (X). This reaction can be carried out in the presence of 2-halogenated aldehyde or 2-halogenated ketone (compound (IX)) in a suitable reaction-inert solvent such as methanol, ethanol, propanol and butanol at a temperature in the range from 25 to 120xc2x0 C., usually from 50xc2x0 C. to 65xc2x0 C. for 8 hours to 72 hours, usually 8 hours to 24 hours. The resulting mixture of the compound (II) and the compound (X) may be subjected to conventional separation techniques to obtain the compound (II). Suitable conventional separation techniques include silica gel column chromatography.
Scheme 7: 
In Scheme 7, a pyridine compound (XV) may be treated with n-BuLi followed by an aldehyde compound (XIX) wherein PG is a suitable protecting group, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Z), or the like, to obtain a compound (XVI). This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, diphenyl ether and 1,4-dioxane. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 100xc2x0 C., usually from xe2x88x92100xc2x0 C. to 80xc2x0 C. for 30 minutes to 24 hours, usually 30 minutes to 10 hours. The compound (XVI) may be treated with an oxidizing agent, for example, pyridinium chlorochromate(PCC), pyridinium dichromate(PDC), manganese dioxide, tetrapropylammonium perruthenate(TPAP), or the like, to obtain a compound (XVII). Also, the compound (XVI) may be subjected to a dimethylsulfoxide oxidation to obtain a compound (XVII). This reaction can be carried out in a suitable reaction-inert solvent such as halogenated hydrocarbons such as chloroform, dichloroethane and 1,2-dichloroethane. This reaction may be carried out at a temperature in the range from 0 to 80xc2x0 C., usually from 25 to 70xc2x0 C. for 5 minutes to 24 hours, usually 15 minutes to 8 hours. Then, the compound (XVII) may be subject to amination according to the similar procedure described in Scheme 2. The obtained amino compound may be subjected to deprotection of an amino-protecting group, to obtain a compound (VIII). The deprotection may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Group and the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 10-142, 309-405). Then, alkylation of amino group in piperidine ring may be carried out under the conventional conditions. The compound may be treated with appropriate alkyl halides(R6xe2x80x94Z) in the presence of a base such as diisopropylethylamine, triethylamine, pyridine, lutidine, potassium carbonate, sodium bicarbonate, sodium carbonate or the like, in a reaction inert solvent such as dichrolomethane, THF or DMF at about 0xc2x0 C. to about 100xc2x0 C. for about 5 minutes to about 48 hours. Then, when R1 is halo, the obtained compound may be subjected to halogenation and deprotection. These reactions may be carried out under the similar conditions described in Scheme 2. Compounds (I) may be prepared by reacting a compound (XVIII) with the compound (IX) under appropriate conditions. This reaction can be carried out in a suitable reaction-inert solvent such as methanol. This reaction may be carried out at a temperature in the range from 25 to 65xc2x0 C., usually from 50xc2x0 C. to 65xc2x0 C. for 30 minutes to 48 hours, usually 30 minutes to 12 hours.
Scheme 8: 
wherein Rxe2x80x2 is C1-3 alkyl; X is NH; and all other symbols are as already defined)
In Scheme 8, the carboxylic acid compound (III) may be coupled with the amine compound (XX) to give an imidazopyridine compound (XXI) wherein X is NH. Then, the compound (XXI) may be subjected to deprotection of the protecting group of nitrogen atom in the piperidinering, followed by alkylation to afford an imidazopyridine compound (I) wherein X is NH.
The coupling reaction may be carried out in the presence of a suitable condensation agent in a reaction-inert solvent. Suitable condensation agents include 1,1xe2x80x2-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), water soluble carbodiumide (WSC), 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylatetriphenylphosphine, diethylcyanophosphonate (DEPC), diphenylphosphorylazide (DPPA), bromotripyrrolidino phosphonium hexafluorophosphate (PyBrop[trademark]), bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), 2-(1-H-benzotriazole-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU) and ethyl chloroformate. Suitable reaction-inert solvents include aqueous or non-aqueous organic solvents such as tetrahydrofuran, N,N-dimethylforrnamide (DMF), dioxane, acetone, dimethoxyethane and acetonitrile; and halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane (preferably dichloromethane). This reaction may be carried out at a temperature in the range from xe2x88x9220 to 80xc2x0 C., usually from 0xc2x0 C. to 30xc2x0 C. for 30 minutes to 100 hours, usually 5 hours to 24 hours.
The obtained amino compound may be subjected to deprotection of an amino-protecting group, to obtain a compound (XXII). The deprotection may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Group and the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 10-142, 309-405). Then, alkylation of amino group in piperidine ring may be carried out under the conventional conditions. The compound may be treated with appropriate alkyl halides(R6xe2x80x94Z) in the presence of a base such as diisopropylethylamine, triethylamine, pyridine, lutidine, potassium carbonate, sodium bicarbonate, sodium carbonate or the like, in a reaction inert solvent such as dichrolomethane, THF or DMF at about 0xc2x0 C. to about 100xc2x0 C. for about 5 minutes to about 48 hours.
Scheme 9:
The carboxylate compounds (IIxe2x80x2), wherein Xxe2x80x2 is may be prepared in the following reaction steps. 
In Scheme 9, the compound (VIII) may be reacted with a compound (XXIII) wherein Xxe2x80x2 is halogen, to obtain a compound (XXIV). This reaction may be carried out in the presence of a base. Example of such bases include: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride. This reaction can be carried out in a suitable reaction-inert solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, dichloromethane, dimethylsulfoxide (DMSO), methylethylketone, methanol, ethanol, propanol and butanol at a temperature in the range from xe2x88x9250 to 100xc2x0 C., usually from xe2x88x9210xc2x0 C. to 50xc2x0 C. for 1 minute to 24 hours, usually 5 minutes to 10 hours. The resulting compound (II) and the compound (XXIV) may be subjected to a cylization to obtain the compound (XXV). This reaction can be carried out in a suitable reaction-inert solvent such as tetrahydrofuran, dimethylformamide (DMF), acetonitrile, dichloromethane, dichloroethane, dimethylsulfoxide (DMSO), methylethylketone, methanol, ethanol, propanol, butanol, iso-butanol, sec-butanol and tert-butanol at a temperature in the range from xe2x88x9250 to 250xc2x0 C., usually from 0xc2x0 C. to 200xc2x0 C. for 1 hour to 100 hours, usually 10 hours to 80 hours.
Then, when R5 is halo, the obtained compound (XXV) may be subjected to halogenation. The compound (XXV) may be treated with phosphorus oxyhalide (POXxe2x80x23) to provide halogenated compound (IIxe2x80x2). This reaction may be carried out at a temperature in the range from 0 to 200xc2x0 C., usually from 20xc2x0 C. to 150xc2x0 C. for 1 minute to 24 hours, usually 5 minutes to 12 hours. Alternatively, compound (IIxe2x80x3) (compound (IIxe2x80x2) wherein R1 is hydrogen) can be prepared by subjecting a compound (XXV) wherein R1 is halo, to catalytic hydrogenation followed by halogenation. The catalytic hydrogenation can be carried out in the presence of hydrogen or hydrogen source such as ammonium formate or triethylsilane and a suitable metal containing catalysts such as palladium, platinum, nickel, platinum oxide and rhodium in a suitable reaction-inert solvent such as methanol. The preferred catalyst is palladium on carbon. This hydrogenation can be carried out at a temperature in the range from 20 to 100xc2x0 C., usually from 25xc2x0 C. to 80xc2x0 C. for 5 minutes to 48 hours, usually 30 minutes to 2 hours. The halogenation of compound (XXVxe2x80x2) may be carried out under the same condition as described in the preparation of compound (IIxe2x80x2).
In addition, starting compounds of formula (V) are known or may be prepared from a known compound according to procedures known to those skilled in the art.
Scheme 10:
An amino compound (XXX) wherein Ra and Rb are C1-4 alkyl and Rc is C1-6 alkyl, may be prepared in the following reaction steps. 
In scheme 10, piperidine compound (XXVI) may be reacted with an epoxide compound (XXVII) to obtain a hydroxy compound (XXVIII). This reaction can be carried out in a suitable reaction-inert solvent such as tetrahydrofuran, dimethylformamide (DMF), acetonitrile, dichloromethane, dichloroethane, dimethylsulfoxide (DMSO), methylethylketone, methanol, ethanol, propanol, butanol, iso-butanol, sec-butanol and tert-butanol at a temperature in the range from xe2x88x9250 to 250xc2x0 C., usually from 0xc2x0 C. to 200xc2x0 C. for 30 minutes to 100 hours, usually 1 hour to 80 hours. This reaction may be carried out in the presense of a methal halide sucha as sodium iodide, potassium iodide and lithium iodide. The conversion of hydroxy compound (XXVIII) to an alkoxy compound (XXIX) may be carried out under the conventional method. The alkylation of a hydroxy group may be carried out under the conventional conditions. The compound may be treated with appropriate alkyl halides(R6xe2x80x94Z) in the presence of a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride or potassium hydride, or the like, in a reaction inert solvent such as diethyl ether, dimthoxyethane, DMSO, THF or DMF at about 0xc2x0 C. to about 200xc2x0 C., usually from 0xc2x0 C. to 200xc2x0 C., for about 5 minutes to about 100 hours, usually 1 hour to 80 hours. Alternatively, hydroxy compound (XXVIII) may be treated with RcO+BF4xe2x88x92 to provide the compound (XXIX). This reaction can be carried out in a suitable reaction-inert solvent such as dichloromethane, dichloroethane, benzene, toluene and nitromethane at a temperature in the range from xe2x88x9250 to 200xc2x0 C., usually from 0xc2x0 C. to 100xc2x0 C. for 30 minutes to 100 hours, usually 1 hour to 80 hours. The obtained compound (XXIX) may be subjected to deprotection of an amino-protecting group, to obtain a compound (XXX). The deprotection may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Group and the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 10-142, 309-405). 
The nicotinate compounds (XXXV) may be prepared in the following reaction steps.
In scheme 11, a pyridine compound (XXXI) may be treated with n-BuLi followed by Rxe2x80x2COZ or Rxe2x80x2CORxe2x80x2 wherein Rxe2x80x2 is C1-3 alkyl or benzyl and Z is halogen, to obtain a compound (XXXIII). This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, diphenyl ether and 1,4-dioxane. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 50xc2x0 C., usually from xe2x88x92100 to 20xc2x0 C. for 5 minutes to 24 hours, usually 15 minutes to 8 hours. Alternatively, the compound (XXXIII) may be prerpareed from the pyridine compound (XXXI) by carboxylation followed by esterification. The pyridine compound (XXXI) may be treated with n-BuLi followed by carbondioxide (gas or dry ice) to obtain a carboxylic acid compound (XXXII). This reaction can be carried out in a suitable reaction-inert solvent. Suitable solvents include, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, diphenyl ether and 1,4-dioxane. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 50xc2x0 C., usually from xe2x88x92100 to 20xc2x0 C. for 5 minutes to 24 hours, usually 15 minutes to 8 hours. The compound (XXXII) may be subjected to esterification to obtain the compound (XXXIII). The esterification may be carried out by a number of standard procedures known to those skilled in the art (e.g., Protective Groups in Organic Synthesis, Third eddition. ed. T. W. Green and P. G. M. Wuts, Wiley-Interscience., pp 373-377.). Typical esterificaion can be carried out with a suitable C1-3 alkylhalide or benzylhalide in the presense of a base in a suitable reaction-inert solvent. Suitable solvents include, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, diphenyl ether, DMF, DMSO, Rxe2x80x2OH and 1,4-dioxane. Suitable bases include, for example, K2CO3, Cs2CO3, NaHCO3 and DBU. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 200xc2x0 C., usually from xe2x88x9210 to 100xc2x0 C. for 1 to 72 hours, usually 2 to 60 hours. The esterification also carried out with trimethylsilyldiazomethane in a suitable reaction-inert solvent. Suitable solvents include, for example, methanol, benzene and toluene. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 200xc2x0 C., usually from xe2x88x9210 to 100xc2x0 C. for 1 minute to 72 hours, usually 0.5 to 60 hours. The esterification also carried out with diazomethane in a suitable reaction-inert solvent. Suitable solvents include, for example, diethyl ether. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 200xc2x0 C., usually from xe2x88x9250 to 100xc2x0 C. for 1 minute to 72 hours, usually 0.5 to 60 hours. Alternatively, the esterification may be carried out with Rxe2x80x2OH, in the presense of a coupling agent and a tertiaryamine in a suitable solvent. Suitable coupling agents include, for example, DCC, WSC, diisoproopylcyanophosphonate (DIPC), BOPCl and 2,4,6-trichlorobenzoic acid chloride. Suitable tertiaryamines include, for example, i-Pr2NEt, Et3N. Suitable solvents include, for example, DMF, THF, diethyl ether, DME, dichloromethane and DCE. This reaction may be carried out at a temperature in the range from xe2x88x92100 to 200xc2x0 C., usually from xe2x88x9250 to 100xc2x0 C. for 1 minute to 100 hours, usually 0.5 to 80 hours. When R1 is halo, the compound (XXXIII) can be treated with halogen or N-halogenated succimide or SELECTFLUOR(trademark) under appropriate conditions, to obtain a compound (XXXIV) wherein R1 is halo. This reaction can be carried out in a suitable reaction-inert solvent such as carboxylic acids (e.g., acetic acid, propionic acid and butylic acid); halogenated hydrocarbons such as chloroform, dichloroethane and 1,2-dichloroethane; amides such as N,N-dimethylformamide and hexamethylphospholictriamide; sulfoxides such as dimethyl sulfoxide; acetonitrile; benzene, toluene, xylene; and pyridine. This reaction may be carried out at a temperature in the range from 0 to 80xc2x0 C., usually from 25 to 70xc2x0 C. for 5 minutes to 24 hours, usually 15 minutes to 8 hours. Then, the compound (XXXIV) may be subject to deprotection of an amino-protecting group, to obtain a compound (XXXV). The deprotection may be carried out in the presence of base (e.g., potassium tert-butoxide, sodium ethoxide and sodium hydroxide) or acids (e.g., hydrochloric acid and sulfuric acid). The deprotection can be carried out in a suitable reaction-inert solvent such as methanol at a temperature in the range from 25 to 80xc2x0 C., usually from 50 to 65xc2x0 C. for 10 minutes to 24 hours, usually 30 minutes to 10 hours.
In addition, starting compound of formula (XXXI) is known or may be prepared from a known compound according to procedures known to those skilled in the art, for example, J. Am. Chem. Soc. (1986), 108(12), 3310-18.
The present invention includes salt forms of the compounds (I) as obtained above. Insofar as the imidazopyridine compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic or organic acids.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned imidazopyridine base compounds of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1.1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate). The acid addition salts can be prepared by conventional procedures.
The compounds of formula (I) of this invention may contain one or more asymmetric centers. Thus, the compounds can exist in separated (+)- and (xe2x88x92)-optically active forms, as well as in the racemic form thereof. The present invention includes all such forms within its scope. Individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic separation in the preparation of the final product or its intermediate.
In addition, when the compounds of this invention form hydrates or solvates they are also within the scope of this invention.
The imidazopyridine compounds of this invention have 5-HT4 receptor binding activity (e.g., agonist or antagonist activities), and thus are useful for the treatment or prevention of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety, cardiovascular disorders such as cardiac failure and heart arryhthmia, or the like in mammalian, especially human.
The compounds of the invention may advantageously be employed in combination with one or more other therapeutic ingredients selected from an antibiotic, anti-fungal and anti-viral agent.
The 5-HT4 receptor binding affinity of the compounds of this invention are determined by the following procedures.
Membrane Preparation
Pig heads were supplied from an abattoir. Striatal tissues were dissected, weighed and homogenized in 15 volumes of 50 mM ice-cold HEPES (pH 7.5) in a Polytron homogenizer (30 sec at full speed). Suspension was centrifuged at 48,000 g and 4xc2x0 C. for 15 min. The resulting pellet was resuspended in an appropriate volume of 50 mM ice-cold HEPES, dispensed into aliquots and stored at xe2x88x9280xc2x0 C. until use.
Bovine heads were also supplied from an abattoir. Striatal tissues were dissected, weighed and homogenized in 20 volumes of 50 mM ice-cold Tris-HCl (pH 7.4) in a Polytron homogenizer (30 sec at full speed). Suspension was centrifuged at 20,000 g and 4xc2x0 C. for 30 min. The resulting pellet was resuspended in 15 volumes of 50 mM ice-cold Tris-HCl, homegenized and centrifuged again in the same way. The final pellet was resuspended in an appropriate volume of 50 mM Tris-HCl, dispensed into aliquots and stored at xe2x88x9280xc2x0 C. until use.
Cerebral cortical tissues were removed from male Sprague-Dawley (SD) rats (Japan SLC), weighed and placed in 10 volumes of 50 mM ice-cold Tris-HCl (pH 7.5). This was homogenized in a Polytron homogenizer (30 sec at full speed) and subsequently centrifuged at 48,000 g and 4xc2x0 C. for 15 min. The resulting pellet was resuspended in 50 mM ice-cold Tris-HCl, homegenized and centrifuged again in the same way. The final pellet was resuspended in an appropriate volume of 50 mM Tris-HCl, dispensed into aliquots and stored at xe2x88x9280xc2x0 C. until use.
The protein concentrations of homogenates were determined by Bradford method or BCA protein method (Pierce) with BSA as a standard.
Binding Assays
Affinity of compounds for pig or bovine 5-HT4 and rat 5-HT3 receptors were assessed with using radiolabeled specific ligands, GR 113808 ({1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}[methyl-3H]-1H-indole-3-carboxylate) and BRL 43694 (1-Methyl-N-(9-[methyl-3H]-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-caboxamide). Compounds were incubated with 25-100 pM of [3H]-GR 113808 (Amersham) and 0.6-1 mg protein of pig or bovine striatal membranes suspended in a final volume of 0.8-1 ml of 50 mM Tris-HCl (pH 7.5). Nonspecific binding was determined with 10-50 xcexcM 5-HT. The binding of 0.3 nM [3H]-BRL 43694 (NEN) was measured using 400 xcexcg protein of rat cortical membranes suspended in a final volume of 500 xcexcl of 50 mM Tris-HCl (pH 7.5). Nonspecific binding was determined with 10 xcexcM 5-HT.
The plates were incubated at room temperature on a plate shaker for 30 min. The assays were stopped by rapid filtration using a Brandell cell harvester through Wallac-B filters pre-soaked in 0.2% poly(ethylenimine) at 4xc2x0 C. for 60-90 min. The filters were washed three times with 1 ml of ice-cold 50 mM HEPES, and were dried in a microwave or at room temperature. They were bagged and heated with meltilex scintillant (Wallac) or soaked in BetaplateScint (Wallac). Receptor-bound radioactivity was quantified using Big-spot counter, Betaplate counter (Wallac) or LS counter (Packard).
Human 5-HT4 Binding
Human 5-HT4(d) transfected HEK293 cells were prepared and grown in-house. The collected cells were suspended in 50 mM HEPES (pH 7.4 at 4xc2x0 C.) supplemented with protease inhibitor cocktail (Boehringer, 1:1000 dilution) and homogenized using a hand held Polytron PT 1200 disrupter set at full power for 30 sec on ice. The homogenates were centrifuged at 40,000xc3x97g at 4xc2x0 C. for 30 min. The pellets were then resuspended in 50 mM HEPES (pH 7.4 at 4xc2x0 C.) and centrifuged once more in the same manner. The final pellets were resuspended in an appropriate volume of 50 mM HEPES (pH 7.4 at 25xc2x0 C.), homogenized, aliquoted and stored at xe2x88x9280xc2x0 C. until use. An aliquot of membrane fractions was used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac).
For the binding experiments, 25 xcexcl of test compounds were incubated with 25 xcexcl of [3H]-GR113808 (Amersham, final 0.2 nM) and 150 xcexcl of membrane homogenate and WGA-SPA beads (Amersham) suspension solutions (10 xcexcg protein and 1 mg SPA beads/well) for 60 minutes at room temperature. Nonspecific binding was determined by 1 xcexcM GR113808 (Tocris) at the final concentration. Incubation was terminated by centrifugation at 1000 rpm. Receptor-bound radioactivity was quantified by counting with MicroBeta plate counter (Wallac).
All compounds prepared in the working examples as described below were tested by this method, and they showed IC50 values from 0.5 nM to 150 nM with respect to inhibition of binding at the 5-HT4 receptor.
Functional Assay:
The presence of 5-HT4 receptors in the rat oesophagus and the ability to demonstrate partial agonism in the TMM preparation are reported in the literature (See G. S. Baxter et al. Naunyn-Schmiedeberg""s Arch Pharmacol (1991) 343: 439-446; M. Yukiko et al. JPET (1997) 283: 1000-1008; and J. J. Reeves et al. Br. J. Pharmacol. (1991) 103: 1067-1072). More specifically, partial agonist activity can be measured according to the following procedures.
Male SD rats (Charles River) weighing 250-350 g were stunned and then killed by cervical dislocation. The oesophagus was dissected from immediately proximal to the stomach (including piece of stomach to mark distal end) up to the level of the trachea and then placed in fresh Krebs"" solution.
The outer skeletal muscle layer was removed in one go by peeling it away from the underlying smooth muscle layer using forceps (stomach to tracheal direction). The remaining inner tube of smooth muscle was known as the TMM. This was trimmed to 2 cm from the original xe2x80x98stomach-endxe2x80x99 and the rest discarded.
The TMMs were mounted as whole xe2x80x98openxe2x80x99 tubes in longitudinal orientation in 5 ml organ baths filled with warm (32xc2x0 C.) aerated Krebs. Tissues were placed under an initial tension of 750 mg and allowed to equilibrate for 60 minutes. The tissues were re-tensioned twice at 15 minute intervals during the equilibration period. The pump flow rate was set to 2 ml/min during this time.
Following equilibration, the pump was switched off. The tissues were exposed to 1 xcexcM carbachol and contracted and reached a steady contractile plateau within 15 minutes. Tissues were then subject to 1 xcexcM 5-HT (this was to prime the tissues). The tissues relaxed in response to 5-HT fairly rapidlyxe2x80x94within 1 minute. As soon as maximal relaxation has occurred and a measurement taken, the tissues were washed at maximum rate (66 ml/min) for at least 1 minute and until the original baseline (pre-carbachol and 5-HT) has returned (usually, the baseline drops below the original one following initial equilibration). The pump flow rate was reduced to 2 ml/min and the tissues left for 60 minutes.
A cumulative concentration-effect-curve (CEC) to 5-HT was constructed across the range 0.1 nM to 1 xcexcM, in half-log unit increments (5-HT curve 1 for data analysis). Contact time between doses was 3 minutes or until plateau established. Tissues responded quicker as concentration of 5-HT in the bath increases. At the end of the curve, the tissues were washed (at maximum rate) as soon as possible to avoid desensitisation of receptors. Pump rate was reduced to 2 ml/min and the tissues left for 60 minutes.
A second CEC was carried outxe2x80x94either to 5-HT (for time control tissues), another 5-HT4 agonist (standard) or a test compound (curve 2 for data analysis). Contact time varied for other 5-HT4 agonists and test compounds and was tailored according to the tissues"" individual responses to each particular agent. In tissues exposed to a test compound, a high concentration (1 xcexcM) of a 5-HT4 antagonist (SB 203,186: 1H-Indole-3-carboxylic acid, 2-(1-piperidinyl)ethyl ester, Tocris) was added to the bath following the last concentration of test compound. This was to see if any agonist-induced relaxation (if present) could be reversed. SB 203,186 reversed 5-HT induced relaxation, restoring the tissue""s original degree of carbachol-induced tone.
Agonist activity of test compounds was confirmed by pre-incubating tissues with 100 nM standard 5HT4 antagonist such as SB 203,186. SB 203,186 was added to the bath 5 minutes before the addition of carbachol prior to curve 2. Tissues must be xe2x80x98pairedxe2x80x99 for data analysis i.e. the test compound in the absence of SB 203,186 in one tissue was compared with the test compound in the presence of SB 203,186 in a separate tissue. It was not possible to carry out a curve 3 i.e. 5-HT curve 1, followed by the test compound curve 2 (xe2x88x92SB 203,186), followed by the test compound curve 3 (+SB 203,186).
Agonist-induced cAMP Elevation in Human 5-HT4(d) Transfected HEK293 Cells
Human 5-HT4(d) transfected HEK293 cells were established in-house. The cells were grown at 37xc2x0 C. and 5% CO2 in DMEM supplemented with 10% FCS, 20 mM HEPES (pH 7.4), 200 xcexcg/ml hygromycin B (Gibco), 100 units/ml penicillin and 100 xcexcg/ml streptomycin.
The cells were grown to 60-80% confluence. On the previous day before treatment with compounds dialyzed FCS (Gibco) was substituted for normal and the cells were incubated overnight.
Compounds were prepared in 96-well plates (12.5 xcexcl/well). The cells were harvested with PBS/1 mM EDTA, centrifuged and washed with PBS. At the beginning of the assay, cell pellet was resuspended in DMEM supplemented with 20 mM HEPES, 10 xcexcM pargyline (Sigma) and 1 mM 3-isobutyl-1-methylxanthine (Sigma) at the concentration of 1.6xc3x97105 cells/ml and left for 15 minutes at room temperature. The reaction was initiated by addition of the cells into plates (12.5 xcexcl/well). After incubation for 15 minutes at room temperature, 1% Triton X-100 was added to stop the reaction (25 xcexcl/well) and the plates were left for 30 minutes at room temperature. Homogenous time-resolved fluorescence-based cAMP (Schering) detection was made according to the manufacturer""s instruction. ARVOsx multilabel counter (Wallac) was used to measure HTRF (excitation 320 nm, emission 665 nm/620 nm, delay time 50 xcexcs, window time 400 xcexcs).
Data was analyzed based on the ratio of fluorescence intensity of each well at 620 nm and 665 nm followed by cAMP quantification using cAMP standard curve. Enhancement of cAMP production elicited by each compound was normalized to the amount of cAMP produced by 1000 nM serotonin (Sigma).
According to the procedures as shown above, the compounds prepared in Examples 1 to 30 were identified as 5HT4 agonists. Introducing an amino group to 5-position of imidazopyridine ring contributed to this agonist activity.
The imidazopyridine compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.3 mg to 750 mg per day, preferably from 10 mg to 500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, for example, a dosage level that is in the range of from 0.06 mg to 2 mg per kg of body weight per day is most desirably employed for treatment of inflammation.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.